In Alzheimer's disease (AD), progressive deposition of amyloid beta-protein (Abeta) fibrils, "amyloid plaques,"[unreadable] occurs in the brain. However, neuronal dysfunction may occur prior to plaque formation. Structure-neurotoxicity[unreadable] studies have revealed progressively smaller toxic assemblies, including protofibrils,[unreadable] paranuclei, and ADDLs. In rodents, Abeta oligomers can inhibit long-term potentiation (LTP), a model for[unreadable] learning and memory. In AD patients, Abeta oligomers are present in levels significantly greater than in agematched[unreadable] normal individuals. Biophysical, cell culture, animal, and human studies thus all support the[unreadable] hypothesis that oligpmerization of Abeta is a key event in AD pathogenesis. If so, then the development of[unreadable] therapeutic strategies depends on elucidation of the mechanism(s) of pathologic protein folding,[unreadable] oligomerization, and higher-order assembly. Continuing efforts in our laboratory to understand the earliest[unreadable] steps in Abeta assembly, Abeta monomer folding and oligomerization, have revealed key structural features.[unreadable] These include turn formation in the Val24-Lys28 region of the unstructured Abeta monomer and interactions[unreadable] among the central hydrophobic cluster (Leu17-Ala21), N-terminus, and C-terminus. The four aims[unreadable] comprising this application seek to test mechanistic hypotheses emanating from these observations.[unreadable] Aim 1. To determine the mechanisms of turn formation in the Val24-Lys28 region of Abeta.[unreadable] a. To determine the role of hydrophobic interactions.[unreadable] b. To determine the role of electrostatic interactions.[unreadable] c. To determine the role of amino-acid turn propensity.[unreadable] Aim 2. To determine the mechanisms of intramolecular folding and early Abeta oligomerization.[unreadable] a. To determine the structural dynamics of central hydrophobic cluster (CHC)-C-terminus interactions.[unreadable] b. To determine the structural dynamics of CHC-N-terminus interactions.[unreadable] c. To determine the effects of alternative turn conformations on Abeta monomer structure and oligomerization.[unreadable] Aim 3. To use O?>N acyl migration chemistry to implement a new, quasisynchronous system for[unreadable] studies of Abeta42 folding and self-assembly.[unreadable] a. To synthesize 26-O-acyl-isoAbeta42 (26-AIAbeta42) and study the time-dependent changes in peptide[unreadable] secondary and quaternary structure following initiation of O?>N acyl migration.[unreadable] b. To use quasielastic light scattering spectroscopy to determine kinetic and thermodynamic parameters[unreadable] of Abeta42 self-assembly.[unreadable] c. To use ion mobility spectroscopy-mass spectrometry to monitor early oligomerization events in Abeta self-assembly.[unreadable] d. To synthesize and study the biophysical and biological behavior of Na-protected 26-AIAbeta42.[unreadable] Aim 4. To determine how structural features shown to be critical in controlling Abeta folding and[unreadable] oligomerization affect peptide neurotoxicity.